1. Field of the Invention
The present invention generally relates to a method for facilitating chemical processing by reducing the amount of solvent needed to conduct a processing step, while allowing for the processing of large amounts of solute material with minimum amounts of solvent. The invention further relates to methods for solvent recycling in conducting extraction, crystallization, deposition, coating, impregnation, and chemical reaction. More particularly, the present invention relates to a method of adjusting the concentration of gaseous fluids in an organic solvent so as to control the solubility of a solute in the organic solvent. In a preferred embodiment, the concentration of the gaseous fluid is repetitively adjusted so as to alternatively expand and contract the solvent volume and to convert the fluid's activity from that of a solvent to that of an anti-solvent.
2. Background of the Related Art
There are numerous methodologies known in the art that require processing of materials with solvents. Solvents are used to solubilize materials for many purposes including, without limitation, extraction, crystallization or precipitation, and reaction. Large amounts of solvent are utilized in chemical processes each year, particularly in the pharmaceutical industry. Because much of this solvent is contaminated during processing steps, equally large amounts of solvent must be disposed of annually. As many solvents are potentially toxic, disposal of these materials has become a large problem for the chemical and pharmaceutical industry.
Solvents are generally liquid in nature. However, gases have been used as solvents, in particular, when the gas is in a supercritical state. The use of gases as solvents proffer the advantage of easy disposal, and if the right gas is used, lower toxicity than many organic solvents.
Gases exist in a supercritical state when they are kept at temperatures and pressures that are simultaneously higher than both their critical temperature and their critical pressure. Many gases in a supercritical state have particularly good extraction capabilities because they display densities very close to those of liquids, with viscosities and diffusivities lying between those of gases and liquids. An extensive discussion of the many uses to which supercritical gases have been applied can be found in McHugh and Kurkonis, Supercritical Fluid Extraction (Buttersworth-Heinemann 1994).
A primary method of crystallizing materials utilizing gases in a supercritical state is known as Rapid Expansion of Supercritical Solutions (RESS) technique. In RESS a solid material which is to be recrystallized is charged to an extraction vessel and an appropriate supercritical fluid in which it is dissolvable is passed through the charge. The high pressure stream, comprised of the gas plus the dissolved solid, leaves the dissolution charge and is depressurized across a pressure reduction/flow control valve or nozzle into a lower pressure gaseous medium. Due to the sudden depressurization and loss of solvent power, particles precipitate and are collected in a collector. The key idea behind RESS is that rapid expansion of a compressed solvent in which a solute is dissolved will lead to the formation of small microparticles or nanoparticles (See, Tom and Debenedetti, 22 J. Aerosol Science 555-584, 1991).
Rapid expansion of a supercritical fluid typically results in very large supersaturation ratios (Mohamed et al., 35 AICHE Journal 325-328, 1989). It is also reported that crystals of various solid substances can be grown in good morphological quality by dissolving the solid substance in a subcritical or supercritical fluid at high pressure, and then slowly, and gradually decreasing the pressure while minimizing heat transfer between the solid-solution system and its environment (See, e.g., U.S. Pat. No. 4,512,846). RESS re-crystallization techniques have been used to recrystallized a number of compounds, including pharmaceutical preparations (See, e.g., U.S. Pat. No. 4,978,752 with respect to crystals of cephem hydrochloride). Such technique has also been used to deposit coatings and films on substrates (See, e.g., U.S. Pat. No. 4,582,731) which discloses methods for solid film deposition and fine powder formation by dissolving solid material in a supercritical fluid solution at elevated pressure and then rapidly expanding the solution through an orifice into a region of relatively low pressure; (see also U.S. Pat. Nos. 4,970,093 and 5,374,305).
The RESS technique is limited in that many compounds are not soluble in non-toxic gases. To overcome this problem a recrystallization technique referred to as the gas anti-solvent (GAS) technique has been proposed. In GAS, the solid solute that is to be recrystallized is first dissolved in an appropriate organic solvent. A suitable gas having high solubility in the organic solvent and little affinity for the solute, is then passed into the organic solvent until sufficient gas is absorbed by the solution for crystallization to occur. The gas therefore acts as an antisolvent. Absorption of the gas into the solvent results in expansion of the liquid and precipitation of the solute. In an alternative approach to classic batch or continuous GAS recrystallization, and in order to enhance control on particle size, recrystallization may be performed by supercritical antisolvent recrystallization (SAS) which consists of continuously spraying a solution containing the solute to be recrystallized into a chamber filled with a supercritical fluid or into a continuous stream of supercritical fluid (See, e.g., Yeo et al. Biotechnology and Bioengineering, 1993, Vol. 41, p. 341). Other alternatives take advantage of high frictional forces (See, PCT Publication WO 95/01221) or high frequency sound waves (See, e.g., U.S. Pat. No. 5,8333,891) to cause the solution to disintegrate into droplets in order to improve crystal yield.
Both RESS and GAS techniques have also been used to effectuate size reduction (See, e.g., Larson and King, 2 Biotechnol. Progress 73-82 (1986) and U.S. Pat. No. 5,833,891 (Issue Date: November 1998)). Such techniques for reducing size have an advantage over conventional milling in that size reduction is non-destructive. Further, many compounds are extremely unstable in conventional milling processes. Mean particle sizes lower than 1 μm, with narrow particle size distribution, have been obtained by means of supercritical sprays (See, e.g., Donsi et al., 65 Acta. Helv. 170-173 (1991)).
Many gaseous fluids are soluble in organic solvents (by “gaseous fluid” is meant (1) a fluid or a mixture of fluids that is gaseous at atmospheric pressure and relatively moderate temperature (≦200° C.), or (2) a fluid that has previously found use as a supercritical fluid). Such fluids are at least partially soluble in the solvent of choice and can be used in either their liquid, gas or supercritical state to reduce the solubility of solid material in solvents. Carbon dioxide (CO2) is highly soluble in most organic solvents. As early as the 1950's, Francis A. W. (J. Phys. Chem, 58, 1099-1114, 1954) reported on the solubility of liquid CO2 in a large variety of organic solvents. Gallager et al. (Am. Chem. Symp. Series No. 406, 1989) and Krukonis et al. (U.S. Pat. No. 5,360,478) both report exploitation of the ability of gaseous CO2 to dissolve in organic solvents to crystallize CO2-insoluble nitroguanadine from an organic solution. Rouanet et al. (U.S. Pat. No. 5,864,923) report a similar batch method to crystallize aerogel material from organic solutions.
Presently used batch and continuous recrystallization, extraction, comminution etc., processes that utilize gaseous fluids in conjunction with organic solvents suffer from a number of disadvantages. For one, present batch and continuous processes do not provide for efficient in-situ recycling of the organic solvent. Following recrystallization, the solute-depleted solvent is not recycled in-situ to allow for re-dissolution of more solute and further recrystallization. Such processes may be extremely inefficient in particular when processing low solubility drugs. For example, for a drug with a solubility of 10 mg/mL in a particular organic solvent, a minimum of 10 liters of the solvent would be required to process 100 g of drug. Large amounts of organic solvents are therefore consumed, making the process environmentally unfriendly, costly and industrially unattractive.